Porcess for production of 2-cyano-3-hydroxy-n-(4-trifluoromethylphenyl)hept-2-en-6-ynamide and process for production of polymorphs thereof

ABSTRACT

A compound (II) is reacted with a compound (III) or a reactive derivative at the carboxyl group thereof to obtain a compound (IV), which is reacted with a mixed acid anhydride of a compound (V) to prepare a compound (I). In recrystallization of the compound (I), temperature for the recrystallization and/or time for the crystal precipitation is controlled to selectively produce A-form crystals, B-form crystals and C-form crystals of the compound (I).

TECHNICAL FIELD

The present invention relates to a novel method for production of2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl) hept-2-en-6-ynamide havingimmunosuppressive activity (hereinafter referred to as “compound (I)”)represented by the formula (I):

and a method for production of polymorphs thereof.

More specifically, the present invention relates to a novel method forpreparing the compound (I) having immunosuppressive activity, and amethod for selectively obtaining anyone of polymorphs comprising A-formcrystals, B-form crystals and C-form crystals of the compound (I).

BACKGROUND ART

The compound (I) is useful for treatment of rheumatoid arthritis, immuneor nonimmune chroic inflammatory diseases such as graft versus hostdisease, reactions by transplantation and uveitis, as well as cancer. Apreparation method thereof has been described in Japanese UnexaminedPatent Publication No. HEI 5-310672 (Patent Document 1).

The compound (I) is specifically described in Preparation Example 14 ofthe above Patent Document 1, in which polymorphs of the compound and amethod for selectively obtaining anyone of the same have not beenreported.

DISCLOSURE OF THE INVENTION

In the preparation method of the compound (I) described in PatentDocument 1, n-butyl lithium, which is highly flammable, is used in anamount as large as 3 equivalent weight with respect to a materialcompound and a reaction temperature needs to be controlled at −78° C. Ithas been a problem since the method is not suitable for manufacture onan industrial scale.

Further, for preparing a safe and effective drug, homogeneity inphysical property of the drug is essential. Even the same compounds mayhave different physical properties if their crystal forms are different.If the crystal form is not controlled, i.e., a single crystal formcannot be formed constantly, the resulting drug may irregularly vary inquality batch by batch. Therefore, manufacture of a substance havinguniform physical properties, that is, control of the crystal form, is anextremely important subject for quality control of the drug.

The present invention has been achieved to solve the above-describedproblem and subject and based on the finding that there exist polymorphsof the compound (I). Accordingly, the present invention provides amethod for preparing the compound (I) suitable for manufacture on anindustrial scale and a method for selectively obtaining anyone of thepolymorphs of the compound (I).

With the intention of establishing a method for preparing the compound(I) free from the above-described problem, the inventors of the presentinvention have carried out eager study and found that theabove-described problem is solved by reacting a compound (IV)represented by the formula (IV):

with a mixed acid anhydride of a compound (V) represented by the formula(V):

, thereby completing the present invention.

Further, in the course of study on a purification method of the compound(I), the inventors of the present invention have also found that A-formcrystals, B-form crystals and C-form crystals of the compound (I) areselectively obtained by controlling the temperature for recrystallizingthe compound (I), thereby completing the present invention.

According to the present invention, provided is a method for preparing acompound (I) represented by the formula:

by reacting a compound (II) represented by the formula:

with a carboxylic acid (III) represented by the formula:

or a reactive derivative at the carboxyl group thereof to give acompound (IV) represented by the formula:

and reacting the resultant compound with a mixed acid anhydride of acompound (V) represented by the formula:

to give the compound (I).

Further, according to the present invention, provided is a method forselectively obtaining A-form crystals, B-form crystals or C-formcrystals of the compound (I) by controlling the temperature forrecrystallizing the compound (I) during the recrystallization of thecompound (I).

BRIEF EXPLANATION OF DRAWINGS

FIG. 1 is an IR spectrum of A-form crystals of the compound (I);

FIG. 2 is an IR spectrum of B-form crystals of the compound (I);

FIG. 3 is an IR spectrum of C-form crystals of the compound (I);

FIG. 4 shows measurement results of a DSC endothermic test of the A-formcrystals of the compound (I);

FIG. 5 shows measurement results of a DSC endothermic test of the B-formcrystals of the compound (I);

FIG. 6 shows measurement results of a DSC endothermic test of the C-formcrystals of the compound (I);

FIG. 7 is an X-ray diffraction pattern of the A-form crystals of thecompound (I);

FIG. 8 is an X-ray diffraction pattern of the B-form crystals of thecompound (I); and

FIG. 9 is an X-ray diffraction pattern of the C-form crystals of thecompound (I).

BEST MODE FOR CARRYING OUT THE INVENTION

The above-described preparation method is represented by the followingequation.

The above preparation method is explained below.

First Step:

A reaction in the first step is conducted by reacting a compound (II)with a compound (III) or a reactive derivative at the carboxyl groupthereof.

The reactive derivative at the carboxyl group of the compound (III) maybe the acid halide, acid azide, acid anhydride, mixed acid anhydride,active amide, active ester and the like.

Concrete examples of the reactive derivative include: acid halide; acidazide; symmetric acid anhydride; asymmetric acid anhydride with acidsuch as substituted phosphoric acid (for example, dialkyl phosphite,phenyl phosphate, diphenyl phosphate, dibenzyl phosphate or halogenatedphosphate), dialkyl phosphate, sulfurous acid, thiosulfuric acid,sulfuric acid, sulfonic acid (for example, methansulfonic acid),aliphatic carboxylic acid (for example, acetate, propionic acid, butyricacid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid or trichloroacetic acid) or aromatic carboxylic acid(for example, benzoic acid); mixed acid anhydride prepared fromchloro(lower)alkyl carbonate or cycloalkyl chlorocarbonate; active amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; active ester (for example, cyanomethyl ester, methoxymethylester, dimethyliminomethyl ((CH₃)₂N⁺═CH⁻) ester, vinyl ester, propargylester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl esteror 8-quinolyl thioester); or ester with N-hydroxy compounds (forexample, N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxy-1H-benzotriazole).

Each of the above-described reactive derivatives may be obtained by ausual method.

The reaction of the first step is usually carried out in a solvent withcooling or heating.

Examples of the solvent used in this reaction include esters such asethyl acetate, ethers such as tetrahydrofuran, diethyl ether anddioxane, aprotic polar solvents such as acetone, acetonitrile,N,N-dimethylformamide and pyridine, halogenated hydrocarbons such as1,2-dichloroethane, chloroform and chlorobenzene, saturated orunsaturated hydrocarbons such as hexane, benzene and toluene or amixture of these solvents.

If the compound (III) is used in the form of free acid in the reactionof the first step, it is preferable to carry out the reaction in thepresence of a normal condensing agent, for example,N,N′-dicyclohexylcarbodiimide,N-cyclohexyl-N′-morpholinoethylcarbodiimide,N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide,N,N′-diethylcarbodiimide, N,N′-diisopropylcarbodiimide,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, N,N′-carbonylbis-(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, ethoxyacetylene,1-alkoxy-1-chloroethylene, trialkylphosphite, ethylpolyphosphate,isopropylpolyphosphate, phosphorus oxychloride (phosphoryl chloride),phosphorus trichloride, diphenylphosphorylazide, thionyl chloride,oxalyl chloride, lower alkyl haloformate (for example,ethylchloroformate, isopropylchloroformate and the like),triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt,2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide inner salt,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate,1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, or in thepresence of a so-called Vilsmeier reagent obtained by a reaction betweenN,N-dimethylformamide and thionyl chloride, phosgene,trichloromethylchloroformate, phosphorus oxychloride or the like.

If the compound (III) is used in the form of free acid, the reaction maybe carried out in the presence of an acid such as inorganic acid,organic acid and Lewis acid.

Examples of the inorganic acid include sulfuric acid, hydrochloric acidand the like. Examples of the organic acid include p-toluenesulfonicacid, benzenesulfonic acid, methansulfonic acid, ethansulfonic acid,sulfosalicylic acid and the like. Examples of the Lewis acid includealuminum chloride, diethyl ether boron trifluoride complex, tintetrachloride, titanium tetrachloride, yttrium triflate, scantiumtriflate and the like. Particularly preferable is p-toluenesulfonicacid.

In general, the reaction in the presence of acid is preferably conductedin a nonpolar solvent which is not mixed with water, e.g., benzene,toluene, xylene, chlorobenzene or the like, with heating, while removingwater generated with the progress of the reaction out of the reactionsystem, or in the presence of a dehydrating agent such as a molecularsieve.

Further, this reaction may be carried out in the presence of aninorganic base such as alkali metal hydrogen carbonates, alkali metalcarbonates and alkali metal hydroxides or in the presence of an organicbase such as tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylaminopyridine, N,N-di(lower)alkylaniline andN,N-di(lower)alkylbenzylamine.

The compound (IV) obtained in the above-described manner may be isolatedand purified by a usual method. However, it may be used in a reaction ofthe following second step without particular isolation or purification.

Second Step:

A reaction in the second step is carried out by reacting the compound(IV) obtained as described above with a mixed acid anhydride of acompound (V) in a solvent.

As the mixed acid anhydride of the compound (V), preferably is a mixedacid anhydride with chloro(lower)alkyl carbonate or cycloalkylchlorocarbonate. Examples of the chloro(lower)alkyl carbonate includemethyl chlorocarbonate, ethyl chlorocarbonate, n-propyl chlorocarbonate,isopropyl chlorocarbonate, n-butyl chlorocarbonate, s-butylchlorocarbonate, t-butyl chlorocarbonate, isoamyl chlorocarbonate andthe like. Examples of the cycloalkyl chlorocarbonate include cyclopentylchlorocarbonate, cyclohexyl chlorocarbonate and the like. Further,bromides, fluorides and iodides converted from these chlorides may alsobe used.

Preparation of the mixed acid anhydride of the compound (V) is generallycarried out in an organic solvent with cooling or heating in thepresence of an inorganic base or an organic base. The inorganic base,organic base and organic solvent may be those shown in the above firststep.

The thus obtained mixed acid anhydride of the compound (V) may beisolated and purified by a usual method. However, it may also be used asit is in a reaction with a compound (IV) without being isolated andpurified.

In the same manner as the above first step, the reaction of the secondstep is generally conducted with cooling or heating in a solvent.

The thus obtained compound (I) may be isolated and purified by a usualmethod, but preferably, it is purified by recrystallization.

Examples of a solvent for the recrystallization include alcohols such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol,t-butyl alcohol and the like, ketones such as acetone, methyl ethylketone and the like, esters such as methyl acetate, ethyl acetate,isopropyl acetate and the like, nitrites such as acetonitrile and thelike, ethers such as tetrahydrofuran, dioxane and the like, as well as amixed solvent of the above-listed solvents capable of being mixed withwater and water as a poor solvent, and a mixed solvent of theabove-listed solvent and a poor solvent, which may be an aliphatichydrocarbon such as n-pentane, cyclopentane, n-hexane, cyclohexane,n-heptane or cycloheptane, an aromatic hydrocarbon such as benzene,toluene, xylene or the like, or disopropyl ether.

Further, as described below, the present invention allows to selectivelyobtain A-form crystals, B-form crystals and C-form crystals of thecompound (I) by controlling the temperature for recrystallization and/ortime for crystal precipitation during the recrystallization of thecompound (I).

In other words, the A-form crystals of the compound (I), characterizedby having an IR (KBr) spectrum of FIG. 1, a DSC endothermic curve ofFIG. 4 and an X-ray diffraction pattern of FIG. 7 and havingcharacteristic peaks at about 6.7, about 13.4 and about 21.50 at 2θ ofthe X-ray diffraction, are obtained by dissolving crystals of thecompound (I) in a solvent, maintaining the solvent at about 55° C. to95° C. with stirring, adding a poor solvent if necessary, and thenfiltering precipitated crystals out.

Further, the B-form crystals of the compound (I), characterized byhaving an IR (KBr) spectrum of FIG. 2, a DSC endothermic curve of FIG. 5and an X-ray diffraction pattern of FIG. 8 and having characteristicpeaks at about 6.2, about 12.5 and about 20.8° at 2θ of the X-raydiffraction, are obtained by dissolving crystals of the compound (I) ina solvent, maintaining the solvent at about 20° C. to about 45° C.,preferably at about 30° C. to about 40° C. with stirring, adding a poorsolvent if necessary, and then filtering precipitated crystals out.

Still further, the C-form crystals of the compound (I), characterized byhaving an IR (KBr) spectrum of FIG. 3, a DSC endothermic curve of FIG. 6and an X-ray diffraction pattern of FIG. 9 and having characteristicpeaks at about 6.2, about 12.4 and about 20.2° at 2θ of the X-raydiffraction, are obtained by dissolving crystals of the compound (I) ina solvent, maintaining the solvent at about 0° C. to about 15° C. withstirring, adding a poor solvent if necessary, and then filteringprecipitated crystals out.

In the above steps, the poor solvent is added when the crystals are hardto be precipitated or the crystallization needs to be accelerated.

However, in the method for selectively obtaining the polymorphsaccording to the present invention, temperature control during thecrystallization is of consequence. Accordingly, the intended crystalform is selectively obtained preferably by dissolving the compound (I)in a solvent, maintaining the solvent at any one of the above-describedtemperatures and adding the poor solvent, rather than by usualrecrystallization.

As the solvent used for preparing the above-described A-form crystals,B-form crystals and C-form crystals, the solvent for therecrystallization of the compound (I) described above may be used.However, in view of yield and the like, particularly preferable arealcohols such as methanol and isopropyl alcohol, or an acetone, acombination of these solvents and water as a poor solvent, or acombination of a solvent such as ethyl acetate and a poor solvent suchas n-heptane.

The above-described A-form crystals are produced by recrystallizationperformed in the temperature range of about 55° C. to about 95° C.

More specifically, if methanol is used as the recrystallization solventto obtain the A-form crystals from crude crystals of the compound (I),for example, methanol may be used in an amount of 0.8 to 80-fold (w/w)of the compound (I) and water as the poor solvent may be used in anamount of 0.5 to 50-fold (v/v) of methanol.

If acetone is used as the recrystallization solvent, acetone may be usedin an amount of 0.6 to 40-fold (w/w) of the compound (I) and water asthe poor solvent may be used in an amount of 0.7 to 10-fold (v/v) ofacetone.

If ethyl acetate is used as the recrystallization solvent, ethyl acetatemay be used in an amount of 2.5 to 10-fold (w/w) of the compound (I) andn-heptane as the poor solvent may be used in an amount of 2 to 50-fold(v/v) of ethyl acetate.

The above-described B-form crystals are produced by recrystallizationperformed in the temperature range of about 20° C. to about 45° C.,preferably about 30° C. to about 40° C.

More specifically, if methanol is used as the recrystallization solventto obtain the B-form crystals from crude crystals of the compound (I),for example, methanol may be used in an amount of 40 to 160-fold (w/w)of the compound (I) and water as the poor solvent may be used in anamount of 0.2 to 10-fold (v/v) of methanol.

If acetone is used as the recrystallization solvent, acetone may be usedin an amount of 3.5 to 60-fold (w/w) of the compound (I) and water asthe poor solvent may be used in an amount of 0.2 to 5-fold (v/v) ofacetone.

If ethyl acetate is used as the recrystallization solvent, ethyl acetatemay be used in an amount of 4.5 to 18-fold (w/w) of the compound (I) andn-heptane as the poor solvent may be used in an amount of 3 to 20-fold(v/v) of ethyl acetate.

The above-described C-form crystals are produced by recrystallizationperformed in the temperature range of about 0° C. to about 15° C.

More specifically, if methanol is used as the recrystallization solventto obtain the C-form crystals from crude crystals of the compound (I),for example, methanol may be used in an amount of 80 to 400-fold (w/w)of the compound (I) and water as the poor solvent may be used in anamount of 0.1 to 5-fold (v/v) of methanol.

If acetone is used as the recrystallization solvent, acetone may be usedin an amount of 7 to 80-fold (w/w) of the compound (I) and water as thepoor solvent may be used in an amount of 0.1 to 5-fold (v/v) of acetone.

If ethyl acetate is used as the recrystallization solvent, ethyl acetatemay be used in an amount of 10 to 45-fold (w/w) of the compound (I) andn-heptane as the poor solvent may be used in an amount of 0.1 to 5-fold(v/v) of ethyl acetate.

If the thus obtained A-form crystals, B-form crystals or C-form crystalsof the compound (I) are suspended in a solvent and stirred with heatingwhile controlling the heating temperature, the A-form crystals, B-formcrystals and C-form crystals of the compound (I) can selectively beconverted to different crystal forms, respectively.

That is, the A-form crystals of the compound (I) can be obtained bysuspending the B-form crystals or C-form crystals of the compound (I) ora mixture thereof in a solvent, maintaining the suspension at about 55°C. to 95° C. with stirring, and then filtering the crystals out of thesuspension.

Alternatively, the B-form crystals of the compound (I) can be obtainedby suspending the A-form crystals of the compound (I) in a solvent,maintaining the suspension at about 20° C. to 45° C. with stirring, andthen filtering the crystals out of the suspension.

As The solvent used for the mutual conversion between theabove-described crystal forms, the solvents for the recrystallization ofthe compound (I) described above may be used. However, in view of yieldand the like, particularly preferable are alcohols such as methanol andisopropyl alcohol, or an acetone, a combination of these solvents andwater as a poor solvent, or a combination of a solvent such as ethylacetate and a poor solvent such as n-heptane.

Time for stirring at a predetermined temperature required for the mutualconversion between the above-described crystal forms is not particularlylimited. However, sufficient time is about 5 hours to about 72 hours ingeneral.

More specifically, in order to convert the B-form crystals or the C-formcrystals of the compound (I) or a mixture thereof into the A-formcrystals, for example, methanol or ethyl acetate may be used. That is,if methanol is used as the solvent, methanol may be used in an amount of8 to 80-fold (w/w) of the B-form crystals or the C-form crystals of thecompound (I) or the mixture thereof and water as the poor solvent may beused in an amount of 0.5 to 50-fold (v/v) of methanol.

If ethyl acetate is used, ethyl acetate may be used in an amount of 2.5to 10-fold (w/w) of the B-form crystals or the C-form crystals of thecompound (I) or the mixture thereof and n-heptane as the poor solventmay be used in an amount of 2 to 50-fold (v/v) of methanol.

Next, in order to obtain the B-form crystals from the A-form crystals ofthe compound (I), for example, methanol or ethyl acetate may be used.That is, if methanol is used as the solvent, methanol may be used in anamount of 40 to 160-fold (w/w) of the A-form crystals of the compound(I) and water as the poor solvent may be used in an amount of 0.2 to10-fold (v/v) of methanol.

If ethyl acetate is used, ethyl acetate may be used in an amount of 4.5to 18-fold (w/w) of the A-form crystals of the compound (I) andn-heptane as the poor solvent may be used in an amount of 3 to 20-fold(v/v) of methanol.

The term “about” used in connection with temperature in the presentspecification indicates that the indicated temperature may vary by ±2°C.

The term “(lower)alkyl” used in the present specification means(C₁-C₅)alkyl.

As a result of analysis on stability of the crystal forms of thecompound (I) based on the measurement results of a DSC endothermic test,it was ascertained that the crystal forms are stable in the order ofB-form crystals>C-form crystals>A-form crystals.

The following Examples are incorporated herein to explain the presentinvention in further detail, to which the scope of the present inventionis not limited.

EXAMPLES Example 1 Preparation of 4-trifluoromethyl cyanoacetoanilide(Compound (IV))

In 700 L of tetrahydrofuran, 63.4 kg of cyanoacetic acid was dissolvedwith stirring in nitrogen atmosphere at room temperature. This solutionwas cooled to 0 to 10° C., and then N-methylmorpholine was addeddropwise with stirring at the same temperature in about an hour. Then,100.0 kg of 4-trifluoromethylaniline was added dropwise. To thisreaction mixture, 91.3 kg of isopropyl chlorocarbonate was addeddropwise with stirring at the same temperature in about an hour.Further, the stirring was continued for 1 to 2 hours.

After the reaction was finished, 200 L of water was added to thereaction mixture, which was stirred and then allowed to stand forseparation. An organic layer (upper layer) was washed with 16.7% brine,and then 400 L of isopropyl alcohol was added thereto, which wasconcentrated under reduced pressure until the liquid amount became 400L. To the condensed solution, 400 L of isopropyl alcohol was added,which was concentrated again under reduced pressure until the liquidamount became 400 L.

To the condensed solution, 100 L of isopropyl alcohol was added at 20 to30° C. with stirring, and then 500 L of water was added dropwise inabout an hour. Then, the stirring was further continued for an hour atthe same temperature. This mixture was cooled to 0 to 10° C. withstirring, and then stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried, to give134.5 kg of the title compound (IV) in a yield of 95.0%.

Example 2 Preparation of2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)hept-2-en-6-ynamide(Compound (I)) from Compound (IV)

In 420 L of acetone, 61.9 kg of 4-pentynoic acid was dissolved withstirring in nitrogen atmosphere at room temperature. This solution wascooled to 10 to 15° C., to which 174.4 kg of potassium carbonate wasadded with stirring. This mixture was heated to 40 to 45° C. and asolution of 120 kg of the compound (IV) obtained in Example 1 in acetone(540 L) was added thereto at the same temperature with heating, and then64.5 kg of isopropyl chlorocarbonate was added dropwise in about anhour. After the dropping was finished, the solution was further stirredfor 30 minutes at the same temperature.

To the reaction solution, 840 L of water was added at 10 to 45° C. withstirring, and then a 17.5% hydrochloric acid solution (mixture of 90 Lof water and 90 L of concentrated hydrochloric acid) was added dropwiseat 20 to 35° C. for 30 minutes. After the precipitate was dissolved, thesolution was further stirred for 30 minutes.

Then, to this solution, a 17.5% hydrochloric acid solution (mixture of45 L of water and 45 L of concentrated hydrochloric acid) was addeddropwise with stirring at the same temperature in an hour, which washeated to 35 to 45° C. and kept stirred for about an hour at the sametemperature. The mixture was cooled to 20 to 30° C. and maintained atsame temperature for about two hours. To this mixture, a 17.5%hydrochloric acid solution (mixture of 45 L of water and 45 L ofconcentrated hydrochloric acid) was further added dropwise at 20 to 35°C. in an hour, which was heated to 35 to 45° C. and stirred at the sametemperature for about an hour, and then maintained at 20 to 30° C. forabout two hours. Precipitated crystals were collected by filtration togive 136.2 kg of the title compound (I) in a yield of 84.0%.

¹H NMR (CDCl₃, 200 MHz) δ: 2.07 (t, J=2.7 Hz, 1H), 2.64 (dt, J=2.7 and7.0 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 7.65 (s, 4H), 7.77 (br.s, 1H),15.59 (br.s, 1H).

IR (ATR method) (cm⁻¹); 3311, 2217, 1627, 1626, 1589, 1554, 1415, 1321,1263, 1243, 1160, 1113, 1072, 841, 658.

Example 3 Preparation of2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)hept-2-en-6-ynamide(Compound (I)) from Compound (IV)

In 618.7 kg of tetrahydrofuran, 87.0 kg of the compound (IV) obtained inExample 1 and 56.1 kg of 4-pentynoic acid were dissolved with stirringin nitrogen atmosphere at 25 to 30° C. To this solution, 158.1 kg ofpulverized potassium carbonate was added with stirring at the sametemperature. While stirring the mixture at 35 to 50° C., a mixture of93.5 kg of isopropyl chlorocarbonate and 77.3 kg of tetrahydrofuran wasadded dropwise in 2 hours. After the dropping was finished, the reactionmixture was stirred at the same temperature for another 2 hours. Afterthe reaction was completed, 677.3 kg of toluene was added to thereaction mixture, which was cooled to 10 to 15° C.

A mixture of 207.1 kg of hydrochloric acid and 783 L of water was addeddropwise to this reaction mixture with stirring, while maintaining thetemperature of the reaction mixture not higher than 25° C. After thedropping was finished, the mixture was further stirred for 5 minutes,and then the stirring was stopped to leave the mixture to stand. Afterthe mixture was separated into two layers, an upper layer was isolated,to which 435 L of 16.7% brine was added and stirred at room temperaturefor 5 minutes. The stirring was stopped and the resulting mixture wasallowed to stand. After the mixture was separated into two layers, anupper layer was isolated and concentrated under reduced pressure toobtain a concentrate of 435 L. To the concentrate, 376.3 kg of toluenewas added, which was concentrated again under reduced pressure to obtaina concentrate of 435 L. While maintaining the solution temperature nothigher than 40° C., 376.3 kg of toluene was added to this concentrate,followed by stirring at 20 to 30° C. for an hour and another stirring at0 to 10° C. for an hour. Then, the resulting mixture was allowed tostand for 2 hours at the same temperature. Precipitated crystals werecollected by filtration and washed sequentially with 150.5 kg oftoluene, 174 L of an aqueous solution of 50% isopropyl alcohol and 174 Lof water, followed by drying at 40° C. under vacuum. Thereby, 98.7 kg ofcrude crystals of the title compound (I) were obtained in a yield of84.0%.

The ¹ HNMR spectrum and IR spectrum of the compound were measured, whichwere in perfect agreement with those of the compound obtained in Example2.

Example 4 Preparation of 2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)hept-2-en-6-ynamide (Compound (I))

In 420 L of acetone, 33.3 kg of cyanoacetic acid was dissolved withstirring in nitrogen atmosphere at room temperature. To this solution,39.6 kg of N-methylmorpholine was added dropwise with stirring at 0 to10° C. in about an hour, to which 60.0 kg of 4-trifluoromethylanilinewas added dropwise. Further, 52.5 kg of isopropyl chlorocarbonate wasadded dropwise to the solution with stirring at the same temperature inan hour, which was then stirred at the same temperature for 1 to 2 hoursto give a reaction product containing the compound (IV).

In nitrogen atmosphere at 25 to 30° C., 43.8 kg of 4-pentynoic acid wasdissolved in 780 L of acetone with stirring. To this solution, 221.3 kgof pulverized potassium carbonate, the reaction product containing thecompound (IV) obtained in the above and 68.5 kg of isopropylchlorocarbonate were added with stirring at the same temperature. Then,the mixture was stirred for 1 to 2 hours while maintaining thetemperature at 40° C. to 55° C.

After the reaction was completed, 1200 L of water was added to thereaction mixture with stirring and the mixture was cooled to 20 to 35°C. To the mixture, a mixture of 214.2 kg of hydrochloric acid and 180 Lof water was added dropwise with stirring while maintaining thetemperature of the reaction mixture at 20 to 30° C. After the droppingwas finished, a mixture of 107.1 kg of hydrochloric acid and 90 L ofwater was further added dropwise with stirring while maintaining thetemperature at 20 to 35° C. Then, the reaction mixture was stirred foran hour while maintaining the temperature thereof at 35 to 45° C.,followed by stirring at 20 to 30° C. for an hour. Precipitated crystalswere collected by filtration and washed sequentially with 180 L of a 70%aqueous acetone solution and 300 L of a 30% aqueous acetone solution.Thereby, 126 kg of crude wet crystals of the compound (I) were obtained.

Part of the wet crystals was dried to measure the ¹HNMR and IR spectra,which were in perfect agreement with those of the compound (I) obtainedin Example 2.

Example 5 Preparation of A-Form Crystals of Compound (I)

5-1

In 50 mL of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was heated to 55° C. withstirring, to which 50 mL of water was added dropwise at the sametemperature in about an hour. After the dropping was completed, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 4.35 g of A-form crystals of the compound (I) in ayield of 87.0%.

The A-form crystals showed endothermic reaction at 175° C. in a DSCendothermic test and indicated characteristic peaks at 6.7, 13.4 and21.5° at 2θ of the X-ray diffraction. FIGS. 1, 4 and 7 show the IR (KBr)spectrum, DSC endothermic curve and X-ray diffraction pattern of thecrystals, respectively.

IR _(KBr) (cm⁻¹); 3310, 2220, 1634, 1592, 1556, 1417, 1329, 1159, 1118,1071, 958, 844, 658, 648.

5-2

In 50 mL of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was refluxed with heating to57° C. with stirring. Then, the resulting mixture was heated to 60° C.while adding 50 mL of water dropwise at the same temperature in about anhour. After the dropping was finished, the mixture was further stirredat the same temperature for an hour. Precipitated crystals werecollected by filtration and dried at 40° C. under vacuum to give 4.12 gof A-form crystals of the compound (I) in a yield of 82.4%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in the above Example 5-1.

5-3

In 50 mL of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was refluxed with heating to57° C. with stirring. Then, the resulting mixture was heated to 65° C.while adding 50 mL of water dropwise at the same temperature in about anhour. After the dropping was finished, the mixture was further stirredat the same temperature for an hour. Precipitated crystals werecollected by filtration and dried at 40° C. under vacuum to give 3.99 gof A-form crystals of the compound (I) in a yield of 79.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in the above Example 5-1.

5-4

In 320 mL of cyclohexane, 16 g of crude crystals of the compound (I)obtained in Example 2 were suspended. The suspension was stirred withheating at a temperature between 75° C. and a boiling point thereof for2 hours. Crystals were collected by filtration, washed with 32 ml ofcyclohexane and dried under reduced pressure to give 15.2 g of A-formcrystals of the compound (I) in a yield of 95.0%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in the above Example 5-1.

5-5

In 20 mL of ethyl acetate, 3 g of crude crystals of the compound (I)obtained in Example 2 were dissolved with heating to 40° C. Thissolution was heated to 60° C. with stirring, to which 200 mL ofn-heptane was added dropwise at the same temperature in about an hour.After the dropping was finished, the mixture was further stirred at thesame temperature for an hour. Precipitated crystals were collected byfiltration and dried at 40° C. under vacuum to give 1.20 g of A-formcrystals of the compound (I) in a yield of 40%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in the above Example 5-1.

5-6

In 500 mL of methanol, 5 g of crude crystals of the compound (I)obtained in Example 2 were dissolved. This solution was heated to 60° C.with stirring, to which 500 mL of water was added dropwise at the sametemperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 2.79 g of A-form crystals of the compound (I) in ayield of 55.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in the above Example 5-1.

Example 6 Preparation of B-Form Crystals of Compound (I)

6-1

To 300 mL of isopropyl alcohol, 10.0 g of crude crystals of the compound(I) obtained in Example 2 were added and dissolved by heating to 78° C.This solution was cooled to 25° C. with stirring, and then the stirringwas continued for 19 hours at the same temperature (22˜25° C.).Precipitated crystals were collected by filtration at the sametemperature, washed with 120 mL of isopropyl alcohol and then driedunder reduced pressure to give 8.87 g of B-form crystals of the compound(I) in a yield of 88.7%.

The B-form crystals showed endothermic reaction at 92 and 175° C. in aDSC endothermic test and indicated characteristic peaks at 6.2, 12.5 and20.8° at 2θ of the X-ray diffraction. FIGS. 2, 5 and 8 show the IR (KBr)spectrum, DSC endothermic curve and X-ray diffraction pattern of thecrystals, respectively.

IR_(KBr) (cm⁻¹); 3311, 2217, 1635, 1614, 1594, 1418, 1399, 1322, 1269,1163, 1125, 1116, 1073, 1020, 970, 843, 666, 659, 592, 525.

6-2

In 50 mL of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was maintained at 25° C. withstirring, to which 50 mL of water was added dropwise at the sametemperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 4.71 g of B-form crystals of the compound (I) in ayield of 94.2%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in the above Example 6-1.

6-3

In 50 mL of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was maintained at 30° C. withstirring, to which 50 mL of water was added dropwise at the sametemperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 4.69 g of B-form crystals of the compound (I) in ayield of 93.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in the above Example 6-1.

6-4

In 50 mL of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was maintained at 35° C. withstirring, to which 50 mL of water was added dropwise at the sametemperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 4.64 g of B-form crystals of the compound (I) in ayield of 92.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in the above Example 6-1.

6-5

To 900 L of acetone, 126 kg of crude wet crystals of the compound (I)obtained in Example 4 were added and dissolved with stirring at roomtemperature. To this solution, 900 L of water was added dropwise at 30to 40° C. with stirring in an hour. The mixture was stirred at the sametemperature for an hour and then cooled to 20 to 30° C. Precipitatedcrystals were collected by filtration and washed with 120 L of a 50%aqueous acetone solution and then dried at 40° C. under vacuum to give86.1 kg of B-form crystals of the compound (I) in a yield of 75.0%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in the above Example 6.

¹H NMR (CDCl₃, 200 MHz) δ: 2.07 (t, J=2.7 Hz, 1H), 2.64 (dt, J=2.7 and7.0 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 7.65 (s,4H), 7.77 (br.s,1H), 15.59(br.s, 1H).

IR (ATR method) (cm⁻¹); 3311, 2217, 1627, 1626, 1589, 1554, 1415, 1321,1263, 1243, 1160, 1113, 1072, 841, 658.

6-6

In 1084 L of acetone, 135.5 kg of crude crystals of the compound (I)obtained in Example 3 were dissolved at room temperature with stirring.The solution was filtered, the residue was washed with 271 L of acetoneand the filtrate and the washings were combined. To this solution, 1355L of water was added dropwise at 30 to 40° C. with stirring in about anhour. Then, the mixture was stirred at the same temperature for an hourand cooled to 20 to 30° C. Precipitated crystals were collected byfiltration, washed with 270 L of a 50% aqueous acetone solution and thendried at 40° C. under vacuum to give 125.4 kg of B-form crystals of thecompound (I) in a yield of 92.5%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in the above Example 6.

6-7

In 30 mL of ethyl acetate, 3 g of crude crystals of the compound (I)obtained in Example 2 were dissolved. This solution was maintained at30° C. with stirring, to which 120 mL of n-heptane was added dropwise atthe same temperature in about an hour. After the dropping was finished,the mixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 1.88 g of B-form crystals of the compound (I) in ayield of 62.7%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in the above Example 6-1.

6-8

In 500 mL of methanol, 5 g of crude crystals of the compound (I)obtained in Example 2 were dissolved. This solution was maintained at30° C. with stirring, to which 500 mL of water was added dropwise at thesame temperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 4.23 g of B-form crystals of the compound (I) in ayield of 84.6%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in the above Example 6-1.

Example 7 Preparation of C-Form Crystals of Compound (I)

7-1

In 100 mL of acetone, 10 g of crude crystals obtained in Example 2 weredissolved with stirring at room temperature. To this solution, 100 mL ofwater was added dropwise at 14 to 15° C. with stirring and the stirringwas continued for 2 hours at the same temperature (15° C.). Precipitatedcrystals were collected by filtration at the same temperature, washedwith 20 ml of a mixture of acetone and water and then dried underreduced pressure to give 9.35 g of C-form crystals of the compound (I)in a yield of 93.5%.

The C-form crystals showed endothermic reaction at 88 and 174.5° C. in aDSC endothermic test and indicated characteristic peaks at 6.2, 12.4 and20.2° at 2θ of the X-ray diffraction. FIGS. 3, 6 and 9 show the

IR (KBr) spectrum, X-ray diffraction pattern and DSC endothermic curveof the crystals, respectively.

IR_(KBr) (cm⁻¹); 3309, 2221, 1590, 1554, 1417, 1388, 1328, 1162, 1118,1072, 1018, 847, 664, 647.

7-2

In 60 mL of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was maintained at 5° C. withstirring, to which 60 mL of water was added dropwise at the sametemperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 4.86 g of C-form crystals of the compound (I) in ayield of 97.2%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theC-form crystals of the compound (I) obtained in the above Example 7-1.

7-3

In 50 ml of acetone, 5 g of crude crystals of the compound (I) obtainedin Example 2 were dissolved. This solution was maintained at 10° C. withstirring, to which 50 mL of water was added dropwise at the sametemperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 4.84 g of C-form crystals of the compound (I) in ayield of 96.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theC-form crystals of the compound (I) obtained in the above Example 7-1.

7-4

In 50 mL of ethyl acetate, 3 g of crude crystals of the compound (I)obtained in Example 2 were dissolved. This solution was maintained at 5°C. with stirring, to which 200 mL of n-heptane was added dropwise at thesame temperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 2.10 g of C-form crystals of the compound (I) in ayield of 70.0%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theC-form crystals of the compound (I) obtained in the above Example 7-1.

7-5

In 1000 mL of methanol, 4 g of crude crystals of the compound (I)obtained in Example 2 were dissolved. This solution was maintained at 5°C. with stirring, to which 1000 mL of water was added dropwise at thesame temperature in about an hour. After the dropping was finished, themixture was further stirred at the same temperature for an hour.Precipitated crystals were collected by filtration and dried at 40° C.under vacuum to give 3.23 g of C-form crystals of the compound (I) in ayield of 80.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theC-form crystals of the compound (I) obtained in the above Example 7-1.

Example 8 Preparation of a-Form Crystals from B-Form Crystals ofCompound (I)

8-1

In 600 mL of n-heptane, 50 g of the B-form crystals of the compound (I)obtained in Example 6 were suspended, heated to 88° C. and kept stirredat the same temperature for about 5 hours. Then, the mixture was cooledto 45° C. with stirring, which was stirred at the same temperature forabout 3 hours. Precipitated crystals were collected by filtration at thesame temperature, washed with 50 mL of n-heptane and then dried at 40°C. under vacuum to give 48.7 g of A-form crystals of the compound (I) ina yield of 97.4%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in Example 5.

8-2

In 400 mL of a 50% aqueous acetone solution, 20 g of the B-form crystalsof the compound (I) obtained in Example 6 were suspended. The suspensionwas heated to 65° C. with stirring, and the stirring was continued for 5hours at the same temperature. The suspension was filtered at the sametemperature to take out crystals, which were dried at 40° C. undervacuum to give 15.96 g of A-form crystals of the compound (I) in a yieldof 79.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in Example 5.

8-3

In 600 mL of cyclohexane, 30 g of the B-form crystals of the compound(I) obtained in Example 6 were suspended. The suspension was heated to72° C. with stirring, and the stirring was continued for 5 hours at thesame temperature. The suspension was filtered at the same temperature totake out crystals, which were washed with 150 mL of cyclohexane anddried at 40° C. under vacuum to give 27.52 g of A-form crystals of thecompound (I) in a yield of 91.7%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in Example 5.

8-4

In a mixture of 20 mL of ethyl acetate and 200 mL of n-heptane, 3 g ofthe B-form crystals of the compound (I) obtained in Example 6 weresuspended. The suspension was heated to 60° C. and stirred at the sametemperature for about 5 hours. Then, precipitated crystals werecollected by filtration at the same temperature and dried at 40° C.under vacuum to give 1.18 g of A-form crystals of the compound (I) in ayield of 39.3%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in Example 5.

Example 9 Preparation of a-Form Crystals from C-Form Crystals ofCompound (I)

9-1

In 200 mL of a 50% aqueous acetone solution, 10 g of the C-form crystalsof the compound (I) obtained in Example 7 were suspended. Thissuspension was heated to 65° C. with stirring, and the stirring wascontinued at the same temperature for 5 hours. The suspension wasfiltered at the same temperature to take out crystals, which were driedat 40° C. under vacuum to give 7.98 g of A-form crystals of the compound(I) in a yield of 79.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in Example 5.

9-2

In 100 mL of a 50% aqueous methanol solution, 5 g of the C-form crystalsof the compound (I) obtained in Example 7 were suspended. Thissuspension was heated to 60° C. with stirring, and the stirring wascontinued for 15 hours at the same temperature. The suspension wasfiltered at the same temperature to take out crystals, which were driedat 40° C. under vacuum to give 3.91 g of A-form crystals of the compound(I) in a yield of 78.2%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theA-form crystals of the compound (I) obtained in Example 5.

Example 10 Preparation of B-Form Crystals from a-Form Crystals ofCompound (I)

10-1

In 100 mL of a 50% aqueous acetone solution, 10 g of the A-form crystalsof the compound (I) obtained in Example 5 were suspended. The suspensionwas maintained at 31° C. with stirring, and the stirring was continuedat the same temperature for 15 hours. The suspension was filtered at thesame temperature to take out crystals, which were dried at 40° C. undervacuum to give 9.38 g of B-form crystals of the compound (I) in a yieldof 93.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in Example 6.

10-2

In 100 mL of isopropyl alcohol, 3 g of the A-form crystals of thecompound (I) obtained in Example 5 were suspended. The suspension wasmaintained at 31° C. with stirring, and the stirring was continued for15 hours at the same temperature. The suspension was filtered at thesame temperature to take out crystals, which were dried at 40° C. undervacuum to give 2.78 g of B-form crystals of the compound (I) in a yieldof 92.7%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in Example 6.

10-3

In a mixture of 30 mL of ethyl acetate and 120 mL of n-heptane, 3 g ofthe A-form crystals of the compound (I) obtained in Example 5 weresuspended. The suspension was maintained at 30° C. with stirring, andthe stirring was continued for 15 hours at the same temperature. Thesuspension was filtered at the same temperature to take out crystals,which were dried at 40° C. under vacuum to give 1.80 g of B-formcrystals of the compound (I) in a yield of 60.0%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in Example 6.

Example 11 Preparation of B-Form Crystals from C-Form Crystals ofCompound (I)

11-1

In 100 mL of a 50% aqueous acetone solution, 5 g of the C-form crystalsof the compound (I) obtained in Example 7 were suspended. The suspensionwas heated to 65° C. with stirring, and the stirring was continued for 5hours at the same temperature. Then, the suspension was cooled to 30° C.and stirred at the same temperature for about 15 hours. The suspensionwas filtered to take out crystals, which were dried at 40° C. undervacuum to give 4.69 g of B-form crystals of the compound (I) in a yieldof 93.8%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in Example 6.

11-2

In a mixture of 20 mL of ethyl acetate and 200 mL of n-heptane, 3 g ofthe C-form crystals of the compound (I) obtained in Example 7 weresuspended. The suspension was heated to 60° C. with stirring, and thestirring was continued for about 5 hours at the same temperature. Then,the suspension was cooled to 30° C. and kept stirred at the sametemperature for about 5 hours. The suspension was filtered to take outcrystals, which were dried at 40° C. under vacuum to give 2.18 g ofB-form crystals of the compound (I) in a yield of 72.6%.

The IR (KBr) spectrum, DSC endothermic curve and X-ray diffractionpattern of the crystals were in perfect agreement with those of theB-form crystals of the compound (I) obtained in Example 6.

INDUSTRIAL APPLICABILITY

The present invention is characterized in that chlorocarbonic estersused as an activating reagent in the preparation method of the compound(I) are decomposed into alcohols and carbon dioxide after the reaction,thereby so-called industrial waste is hardly generated. Further, sincethe preparation method of the compound (I) according to the presentinvention does not require severe reaction conditions, general-purposefacilities can be used. Accordingly, the preparation method is moresuitable for the production of the compound (I) on an industrial scalethan a conventional method for preparing the compound (I).

Still further, according to the present invention, A-form crystals,B-form crystals and C-form crystals of the compound (I) may selectivelybe produced with efficiency by controlling temperature for therecrystallization and/or time for the crystal precipitation during therecrystallization of the compound (I).

1. A method for preparing a compound (I) represented by the formula:

which is characterized by reacting a compound (IV) represented by theformula:

with a mixed acid anhydride of a compound (V) represented by theformula:

to give the compound (I).
 2. A method for preparing a compound (I)represented by the formula:

which is characterized by reacting a compound (II) represented by theformula:

with a carboxylic acid (III) represented by the formula:

or a reactive derivative at the carboxyl group thereof to give acompound (IV) represented by the formula:

and reacting the resultant compound with a mixed acid an hydride of acompound (V) represented by the formula:

to give the compound (I).
 3. The preparation method according to claim 1or 2, wherein the mixed acid anhydride of the compound (V) is a mixedacid anhydride with chloro(lower)alkyl carbonate.
 4. A method forpreparing A-form crystals of the compound (I) described in claim 1 or 2,which is characterized by dissolving the compound (I) in a solvent,maintaining the resultant solution at a temperature from about 55° C. toabout 95° C. while stirring, adding with a poor solvent, if necessary,and then isolating the precipitated crystals.
 5. A method for preparingB-form crystals of the compound (I) described in claim 1 or 2, which ischaracterized by dissolving the compound (I) in a solvent, maintainingthe resultant solution at a temperature from about 20° C. to about 45°C. while stirring, adding with a poor solvent, if necessary, and thenisolating the precipitated crystals.
 6. A method for preparing C-formcrystals of the compound (I) described in claim 1 or 2, which ischaracterized by dissolving the compound (I) in a solvent, maintainingthe resultant solution at a temperature from about 0° C. to about 15° C.while stirring, adding with a poor solvent, if necessary, and thenisolating the precipitated crystals.
 7. The method according to any oneof claims 4 to 6, wherein the poor solvent is selected from an aliphatichydrocarbon such as n-pentane, cyclopentane, n-hexane, cyclohexane,n-heptane or cycloheptane; an aromatic hydrocarbon such as benzene,toluene or xylene; an ethers such as diisopropyl ether; and water. 8.The method according to claim 5, which is characterized in that thesolution is maintained at a temperature from about 30° C. to about 40°C.
 9. The method according to any one of claims 4 to 6 and 8, whereinthe solvent is acetone, and water is added as the poor solvent.
 10. Themethod according to any one of claims 4 to 6 and 8, wherein the solventis methanol, and water is added as the poor solvent.
 11. The methodaccording to any one of claims 4 to 6 and 8, wherein the solvent isethyl acetate, and n-heptane is added as the poor solvent.
 12. Themethod according to claim 5, wherein the solvent is isopropyl alcoholand no poor solvent is added.
 13. A method for converting of B-formcrystals or C-form crystals of the compound (I) described in claims 5 or6 respectively, or mixture thereof into A-form crystals of the compound(I), which is characterized by suspending B-form crystals or C-formcrystals of the compound (I) or mixture thereof in a solvent andstirring the resultant suspension at a temperature from about 55° C. toabout 95° C.
 14. A method for converting of A-form crystals of thecompound (I) described in claim 4 into B-form crystals of the compound(I), which is characterized by suspending B-form crystals in a solventand stirring the resultant suspension at a temperature from about 20° C.to about 45° C.
 15. The method according to claim 13 or 14, wherein thesolvent is an aqueous acetone, aqueous methanol, isopropyl alcohol,cyclohexane, n-heptane or a mixture of ethyl acetate and n-heptane. 16.The method according to claim 15, wherein the stirring is continued forabout 5 hours to about 72 hours.